In Burkitt's lymphoma, c-myc is consistently found to be transcriptionally activated and overexpressed. More than 80% of c-Myc reduced B-lymphomas exhibit inactivation of Arf/p53, which correlates with cancer cell invasiveness, resistance to anticancer agents, and poor prognosis. Targeting c-Myc might be an effective approach to control B-lymphomas, but this strategy has a potential risk because loss of c-Myc has a major negative impact on physiological function and viability of normal cells. C-Myc directly and positively regulates transcription of the Cdk4 gene, which phosphorylates Rb and related pocket-binding proteins, promoting G1 cell cycle progression. Our previous studies showed that elimination of Cdk4 minimally affects normal cell proliferation, but completely abrogates transformation of murine fibroblasts induced by Ras activation and c-Myc overexpression or Arf/p53 disruption. These data suggest that Cdk4 and/or closely related Cdk6 can be a superb therapeutic target for treatment of malignancies with overexpression of c-Myc and inactivation of Arf/p53, such as B-lymphoma. The long-term goal is to develop therapeutic strategies to target the cell cycle machinery, specifically in cancer or pre-cancer lesions of patients. We hypothesize that Cdk4/6 play an essential role in B-lymphoma, and that Cdk4/6 silencing can inhibit proliferation of B-lymphoma without detrimental effects on normal cell cycle progression and development. The specific aims are: (1) Determine whether Cdk4/6 plays an essential role in tumorigenicity and development of B-lymphoma driven by c-Myc by examining the effect of Cdk4/6 suppression on the B-lymphoma; (2) Determine whether Cdk4/6-siRNAs can be used as therapeutic agents in the mouse models; (3) Dissect the molecular mechanism of interaction of Cdk4/6 and B-lymphoma. The presented program takes innovative approaches that should lead us to a better understanding of interaction between Cdk4/6 and B-lymphoma, and should provide new strategies for more effective therapy in B-lymphoma. [unreadable] [unreadable] [unreadable]